Monocyte chemotactic protein 1 regulates oral tolerance induction by inhibition of T helper cell 1-related cytokines.
Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune demyelinating disease of the central nervous system that serves as an animal model for multiple sclerosis. Antigen-specific tolerance regimens, including oral tolerance, have been used prophylactically to prevent development of acute EAE as well as a number of other autoimmune diseases. Two mechanisms have been proposed to explain the immunologic basis for disease inhibition: bystander immune suppression and clonal anergy/deletion. This report demonstrates a novel mechanism for monocyte chemotactic protein (MCP)-1 as a regulatory factor of oral tolerance. Oral administration of proteolipid protein peptide (PLP139-151) increased MCP-1 expression in the intestinal mucosa, Peyer's patch, and mesenteric lymph nodes. Increase in MCP-1 expression resulted in downregulation of mucosal interleukin (IL)-12 expression with concomitant increase in mucosal IL-4 expression. Functionally, MCP-1 upregulation was shown to regulate oral tolerance induction by the ability of antibodies to MCP-1 to inhibit tolerance induction. The anti-MCP-1 abrogation of oral tolerance induction also resulted in restoration of mucosal IL-12 expression as well as peripheral antigen-specific T helper cell 1 responses. These results demonstrate a novel and important role for MCP-1 in the regulation or oral tolerance for the prevention and treatment of autoimmune disease.
Karpus
W J
WJ
Department of Pathology, Immunobiology Center, Robert H. Lurie Cancer Center, and Institute for Neuroscience, Northwestern University Medical School, Chicago, Illinois 60611, USA. w-karpus@nwu.edu
Kennedy
K J
KJ
Kunkel
S L
SL
Lukacs
N W
NW
D000284:Administration, Oral; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage*; D018932:Chemokine CCL2 / Q000502:physiology*; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D018928:Immunity, Mucosal / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology*; D010581:Peyer's Patches / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D015854:Up-Regulation
D001324:Autoantigens; D018932:Chemokine CCL2; D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma